Short peptide sequences mimic HLA-DM functions

Chou, Chih Ling; Mirshahidi, Saied; Su, Katherine W.; Kim, Ae Ryon; Narayan, Kedar; Khoruzhenko, Stanislav; Xu, Minzhen; Sadegh‐Nasseri, Scheherazade

doi:10.1016/j.molimm.2007.10.033

Cited by 29 publications

(26 citation statements)

References 51 publications

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“…On MHC class II molecules, short dipeptides that bind into the P1 pocket catalyze the exchange of prebound peptides for exogenous ones (6,7). Because we found previously that certain dipeptides bind to and stabilize the MHC class I proteins H-2K b (K b ) and HLA-A*02:01 (A2) in the absence of high-affinity fulllength peptides (5), we asked whether such dipeptides also promote peptide exchange on MHC class I.…”

Section: Resultsmentioning

confidence: 99%

“…Peptide exchange on MHC class II molecules is triggered by HLA-DM (in humans) and H-2M (in mice) through the displacement of a peptide anchor side chain from the P1 pocket (23). The action of DM can be mimicked by small molecules, such as dipeptides, phenol, or adamantane, that occupy the P1 pocket (6,7,24). Because small-molecule peptide-exchange mechanisms on class I and class II are similar (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Dipeptides catalyze rapid peptide exchange on MHC class I molecules

Saini

Schuster

Ramnarayan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Peptide ligand selection by MHC class I molecules, which occurs by iterative optimization, is the centerpiece of immunodominance in antiviral and antitumor immune responses. For its understanding, the molecular mechanisms of peptide binding and dissociation by class I molecules must be elucidated. To this end, we have investigated dipeptides that bind to the F pocket of class I molecules. We find that they accelerate the dissociation of prebound peptides of both low and high affinity, suggesting a mechanism of action for the peptide-exchange chaperone tapasin. Peptide exchange on class I molecules also has practical uses in epitope discovery and T-cell monitoring.peptide exchange | MHC tetramers | tapasin | immunotherapy | dipeptides M HC class I proteins, which are expressed on the surface of nucleated cells of higher vertebrates, present intracellular peptides to cytotoxic T lymphocytes (CTLs). To bind to class I, a peptide must fulfill allotype-specific length and sequence requirements: Hydrogen bond networks that hold the N and C termini usually restrict peptide length to 8-10 amino acids, and side chains at defined positions (anchor residues) must fit into specificity pockets at the bottom of the binding groove (1).Cellular selection of antigenic peptides that conform to these requirements is an important step in immunodominance, the focusing of the adaptive immune system on a few epitopes in an immune response to viruses and cancer (2). This selection is thought to occur via iterative optimization, usually with the help of the peptide-exchange chaperone tapasin (3). Despite longstanding investigations, the molecular mechanism of peptide binding, dissociation, and tapasin-mediated exchange has remained elusive (4), in part because of the lack of structural information about peptide-free class I proteins.To explore the molecular mechanism of peptide binding and dissociation, we have searched for small molecules that can bind to class I and modulate the binding of high-affinity peptides. We have demonstrated previously that dipeptides of appropriate sequence bind to class I molecules, presumably to the F pocket, and support their folding (5), and we now show that they also dramatically accelerate the dissociation of prebound peptides and their exchange for exogenous peptides in a function analogous to that of tapasin. ResultsOn MHC class II molecules, short dipeptides that bind into the P1 pocket catalyze the exchange of prebound peptides for exogenous ones (6, 7). Because we found previously that certain dipeptides bind to and stabilize the MHC class I proteins H-2K b (K b ) and HLA-A*02:01 (A2) in the absence of high-affinity fulllength peptides (5), we asked whether such dipeptides also promote peptide exchange on MHC class I. We expressed recombinant A2 in Escherichia coli, folded it in vitro with the peptide NLVPMVATA, removed the free peptide by gel filtration, and added NLVPK FITC VATV (in which the lysine side chain is labeled with FITC in a position that does not interfere with binding to A2). The bi...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dipeptides catalyze rapid peptide exchange on MHC class I molecules

Saini

Schuster

Ramnarayan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…More recently, DM mimics capable of catalyzing peptide exchange have been described. These simple organic chemicals or peptidic molecules operate at neutral pH and enhance T cell activation (26,27,(43)(44)(45). Interestingly, a better loading was obtained by combining n-propanol and DMY, suggesting that the former acts in a DM-independent and -dependent fashion.…”

Section: Discussionmentioning

confidence: 99%

Forced Expression of HLA-DM at the Surface of Dendritic Cells Increases Loading of Synthetic Peptides on MHC Class II Molecules and Modulates T Cell Responses

Pezeshki

Côté

Azar

et al. 2011

The Journal of Immunology

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Adoptive transfer of autologous dendritic cells (DCs) loaded with tumor-associated CD4 and CD8 T cell epitopes represents a promising avenue for the immunotherapy of cancer. In an effort to increase the loading of therapeutic synthetic peptides on MHC II molecules, we used a mutant of HLA-DM (DMY) devoid of its lysosomal sorting motif and that accumulates at the cell surface. Transfection of DMY into HLA-DR+ cells resulted in increased loading of the exogenously supplied HA307–318 peptide, as well as increased stimulation of HA-specific T cells. Also, on transduction in mouse and human DCs, DMY increased loading of HEL48–61 and of the tumor Ag-derived gp100174–190 peptides, respectively. Interestingly, expression of DMY at the surface of APCs favored Th1 differentiation over Th2. Finally, we found that DMY− and DMY+ mouse APCs differentially stimulated T cell hybridomas sensitive to the fine conformation of peptide–MHC II complexes. Taken together, our results suggest that the overexpression of HLA-DMY at the plasma membrane of DCs may improve quantitatively, but also qualitatively, the presentation of CD4 T cell epitopes in cellular vaccine therapies for cancer.

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“…However, following studies failed to confirm this initial correlation suggesting a more complex landscape of effects Belmares et al, 2002;Pashine et al, 2003;Stratikos et al, 2002;Stratikos et al, 2004). Kinetic stability appears to be a crucial factor, possibly more important than thermodynamic stability of the complex (Hall et al, 2002;Zarutskie et al, 2001;Weber et al, 1996;Chou et al, 2008;Nicholson et al, 2006). Three features of the MHCII-peptide interaction appear to be responsible for DM mediated editing.…”

Section: Editing Of Antigenic Peptides In the Mhc Class II Pathway By Dmmentioning

confidence: 99%

“…Although both molecules operate in separate pathways, it appears that they employ similar strategies to catalyze and edit antigenic peptide loading onto MHC class I and class II molecules respectively. Both can act as chaperones to empty MHC molecules and help maintain them in a state that peptides can readily bind (Zarutskie et al, 2001;Vogt et al, 1997b;Kropshofer et al, 1997a;Chou et al, 2008;Cabrera, 2007;Rizvi and Raghavan, 2006;Schoenhals et al, 1999). Both tapasin and DM affect a series of hydrogen bonds between the antigenic peptide and the MHC molecule.…”

Section: Mhc Class I and Class Ii Pathway Parallels: Tapasin And Dmmentioning

confidence: 99%

Cellular Mechanisms that Edit the Immunopeptidome

Georgiadou¹,

Stratikos

2009

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The adaptive immune response relies on the ability of T-lymphocytes to recognize small antigenic peptides presented on the cell surface by specialized receptors of the Major Histocompatibility Complex (MHC). These peptides are either generated by the degradation of intracellular proteins (MHC class I pathway) or by the degradation of internalized extracellular proteins (MHC class II pathway and cross-presentation pathway). The number of proteins that can be degraded by these pathways runs to the thousands leading to a staggering number of possible peptide fragments. A small subset of these peptides is selected by the cell's processing and presentation mechanisms to be presented on the cell surface by MHC molecules and has been defined as the immunopeptidome. The peptide sequences that comprise the immunopeptidome control the immune response and variations of this peptide repertoire are key to understanding the host's ability to fight pathogens, immune response to cancer as well as predisposition to autoimmunity and allergies. In the last few years it has been established that the composition of the immunopeptidome is regulated by specific cellular mechanisms that influence qualitative and quantitative aspects of the cellular immune response in a process that has been described as antigenic peptide editing. This review explores the current knowledge on these cellular mechanisms and discusses the parallels between editing the MHC class I and class II immunopeptidomes.

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Short peptide sequences mimic HLA-DM functions

Cited by 29 publications

References 51 publications

Dipeptides catalyze rapid peptide exchange on MHC class I molecules

Dipeptides catalyze rapid peptide exchange on MHC class I molecules

Forced Expression of HLA-DM at the Surface of Dendritic Cells Increases Loading of Synthetic Peptides on MHC Class II Molecules and Modulates T Cell Responses

Cellular Mechanisms that Edit the Immunopeptidome

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